Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC

Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC

Ashish M. Kamat, MD, MBBS, FACS

Professor of Urologic OncologyWayne B. Duddlesten Professor of Cancer Research

President, International Bladder Cancer Group

NMIBC is a heterogeneous group of tumors

Risk categories are not uniform

Lancet, June 2016

European Association of Urology

v

American Urological Association

Common Definition

Adopted from IBCG,Brausi Metal.2011

• Low Risk§ Solitary, primary, TaLG < 3 cm

• High Risk§ Any T1 or any high grade (Ta, T1), including CIS§ Progression main concern

• Intermediate Risk§ Everything else (i.e. recurrent/multiple TaLG)§ Recurrence main concern

Adjuvant Therapy

Intermediate Risk Tumors

Kamat et al, J Urol, 2014

Intermediate Risk Tumors (Low Grade)

High Risk Tumors

~ 1.2 Million Doses of BCG used globally for Bladder Cancer

BCG is the ORIGINAL

Myth #1

BCG does not reduce progression rates(only reduces recurrences)

Study Publ YearAuthor and Group

Events / PatientsNo BCG BCG

Statistics(O-E) Var.

OR & CI:(BCG No BCG)

|1-OR|% ± SD

ProgressionAll Studies With Maintenance

1991 Pagano (Padova) 11 / 63 3 / 70 -4.4 3.1


1987 Badalament (MSKCC) 6 / 46 6 / 47 -0.1 2.6


2000 Lamm (SW8507) 102 / 192 87 / 192 -7.5 24.1


2001 Palou 2 / 61 3 / 65 0.4 1.2


1996 Rintala (Finnbl 2) 3 / 90 3 / 92 0 1.5


1995 Rintala (Finnbl 2) 4 / 40 2 / 28 -0.5 1.3


1995 Lamm (SW8795) 24 / 186 15 / 191 -4.8 8.8


1999 Malmstrom (Sw-N) 22 / 125 15 / 125 -3.5 7.9


2001 Nogueira (CUETO) 8 / 127 10 / 247 -1.9 3.9


1991 Rintala (Finnbl 1) 2 / 58 3 / 51 0.7 1.2


2001 de Reijke (EORTC) 18 / 84 10 / 84 -4 5.9


2001 vd Meijden (EORTC) 19 / 279 24 / 558 -4.7 9.1


1982 Brosman (UCLA) 0 / 22 0 / 27 0 0


1990 Martinez-Pineiro 4 / 109 1 / 67 -0.9 1.2


1999 Witjes (Eur Bropir) 2 / 25 1 / 28 -0.6 0.7


1997 Jimenez-Cruz 7 / 61 6 / 61 -0.5 2.9

All Studies With Maintenance

1994 Kalbe 2 / 35 0 / 32 -1 0.5

PrAll Studies With Maintenance

1991 Kalbe 2 / 17 0 / 21 -1.1 0.5

All

1993 Melekos (Patras) 7 / 99 2 / 62 -1.5 21988 Ibrahiem (Egypt) 12 / 30 5 / 17 -1.1 2.6

Total 257 / 1749 196 / 2065 -36.8 80.9(14.7 %) (9.5 %)

27% ±9reduction

0.0 0.5 1.0 1.5 2.0BCG No BCGTest for heterogeneitybetter betterc 2

=9.73, df=18: p=0.9

Treatment effect: p=0.00004

Intravesical BCGAnalysis of Progression in 20 Controlled Trials

Sylvester, 2002

BCG reduces progression only when maintenance is usedMeta analysis of 24 RCT of BCG with 4,863 pts

Sylvester RJ: J Urol. 2002, 168:1964-70

Myth #2

Optimal maintenance schedule unknown(induction alone is enough)

BCG Maintenance: Not Created EqualOnly SWOG protocol shows clear benefit

Kamat & Porten, Eur Urol, 2014

Optimal BCGUrinary IL-2 Assay

Induction Re-induction

De Reijke, 1999

Why timing is important

Adapted from Lamm, JU 2000



3 month eval



6 month eval



64% of ‘failures’ salvaged with 3 weeks of BCG

6 month eval

Key Fact

Duration appears to be more crucial than dose

EORTC30962 – FD vs LD, 1 yr vs 3 yr

Oddens et al, Eur Urol, 2013

Four groups (5 year Disease Free Rates)

3 year @ full dose: 64.2%3 year @ 1/3rd dose: 62.6%

1 year @ full dose: 58.8%1 year @ 1/3rd dose: 54.5%

FD @ 3 yrs was superior to LD @ 1 yr was (p = 0.01)

Myth #3

BCG is only indicated for high grade disease

EORTC 309113 Week Maintenance BCG vs Epirubicin

Rec reduced with BCGMaintenance (p<0.0001)

Mets reduced with BCGMaintenance (p=0.046)

Overall survival (& DSS)Improved with BCG Maint.

(P=0.023) 837 randomized pts without CIS followed for 9.2 yrs.497 intermediate risk (LOW GRADE) - as good/better benefit vs high risk

Sylvester RJ: Eur Urol. 12: 2009

Myth #4

Most patient cannot tolerate full course of BCG

BCG is well tolerated

EORTC 30962 � Comparison of full dose vs 1/3rd dose BCG for 1 year vs 3

years� 1355 patients; median follow-up of 7.1 yrs,

� < 10% patients discontinued due to toxicity

International IPD Survey� 971 patients

� only 5.2% discontinued BCG maintenance due to toxicity.

Oddens J et al, Eur Urol, 2012; Witjes et al, BJUI, 2012

� Minimize fluid intake before instillation

� Start with empty bladder� Inspect voided urine for visible

hematuria � (routine urinalysis/dipstick not

necessary)

� Catheterize atraumatically� Minimize lubricant (to avoid

BCG clumping)� Avoid lidocaine (acidity

degrades BCG)

� No rotisserie-style turning� Statins/aspirin therapy okay� Antispasmodics for local

symptoms� Antipyretics for influenza-like

symptoms� Give 1 dose of quinolone 6

hours after BCG� Suspected BCGosis/BCG sepsis

needs prompt workup and aggressive therapy

Myth #5

BCG is not effective in older patients

BCG fails older patients?� Kanematsu et al – higher recurrence and reduced

PPD in patients >80 yr with BCG [Hinyokika Kiyo 1998]

� Joudi et al – non-randomized study, 22% lower DSS in patients >80 yr with BCG + interferon [J Urol 1996]

� Other smaller reports : claimed lower efficacy of intravesical immunotherapy in elderly patients � No control group for comparison.

Kamat & Lamm, Eur Urol, 2014

EORTC 30911 – Sub Analysis


Patients >70 yr had a shorter time to progression (p=0.028), OS (p<0.001), and NMIBC-specific survival (p=0.049) but similar time to recurrence compared with younger patients.

EORTC 30911 – Sub AnalysisBCG was still more effective than epirubicin for all four end points considered; including in patients >70 yr


Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC


Professor of Urologic OncologyWayne B. Duddlesten Professor of Cancer Research

President, International Bladder Cancer Group


[email protected]

Thank You

@UroDocAsh

Myths and Mysteries Surrounding Adjuvant Therapy for NMIBC

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